Pharmacological inhibition of the Notch pathway enhances the efficacy of androgen deprivation therapy for prostate cancer

Although androgen deprivation therapy (ADT) is a standard treatment for metastatic prostate cancer, this disease inevitably recurs and progresses to ADT-resistant stage after this therapy. Accordingly, understanding the mechanism of resistance to ADT and finding new approach to enhance the efficacy of ADT may provide a major benefit to PCa patients. In our study, we found upregulated expression of Notch receptors is positive associated with ADT-resistance progression. Using fluorescent Notch signaling reporter system, we observed that endogenous Notch signaling could be activated after treatment of androgen deprivation in LNCaP cells via activation of Notch3. In addition, exogenous activation of the Notch signaling though Dox-induced overexpression of any Notch intracellular domains (NICD1-4) could enhance the resistance of PCa cells to ADT under ex vivo 3D culture conditions and upregulate expression of ADT resistance-associated phospho-p38 and Bcl-2 in LNCaP cells. As a result, pharmacological inhibition of the Notch pathway using -secretase inhibitor (GSI), DAPT, downregulated both phospho-p38 and Bcl-2 expression and significantly enhanced the efficacy of ADT in androgen sensitive PCa cells with impaired proliferation and 3D colony formation, increased apoptosis and remarkable inhibition of tumor growth in murine subcutaneous xenograft model. These results indicate that activated Notch signaling contributes to ADT resistance, and suggest that inhibition of the Notch pathway may be a promising adjuvant therapy of ADT for PCa. What's new? Metastatic prostate cancer commonly is treated with androgen deprivation therapy (ADT). ADT can effective delay disease progression for several years, though tumors eventually develop resistance. This study sheds light on mechanisms of ADT resistance, showing in LNCaP prostate cancer cells that Notch receptors are upregulated after ADT, with Notch signaling linked to ADT resistance. In ex vivo 3D culture, exogenous activation of Notch intracellular domains enhanced resistance and expression of phospho-38 and Bcl2. Pharmacological blockade of the Notch pathway improved ADT efficacy in vitro and in vivo, suggesting that Notch signaling is a potential target for adjuvant therapy to ADT.